tbuckley/cabot-search huggingface dataset:
P07.09.A Intra operative mapping and monitoring of the cortico-spinal tracts with neurophysiological assessment in intra axial brain tumor resection
Authors: l oxman, s emanuel, o zarchi
Journal: Neuro-Oncology (2022)

Abstract Background Preserving motor function is a major challenge in surgery for intra axial brain tumors. In the past two decades, rapid developments in neuroscience, have fueled the growth of intraoperative neurophysiologic monitoring and mapping. Neurophysiological motor mapping allows identification with subsequent preservation of functionally viable nervous tissue. Currently, continuous mapping is typically achieved by electrostimulating via connection to a surgical tool, )e.g., suction(, establishing a stimulation threshold for inducing a motor response, and stopping the resection when reaching motor responses at low electrostimulation levels of 2-10 mA. While most authors report the use of monopolar electrostimulation, which tends toward high sensitivity - low specificity, others report the use of bipolar electrostimulation, which tends toward high specificity - low sensitivity results. Here we report an investigation of the differences between monopolar and bipolar electrostimulation for motor mapping, comparing the sensitivity and specificity of the two methods. Material and Methods Gross motor function was evaluated preoperative and 1d postoperative. During the resection, a minimal monopolar electrostimulation threshold was determined, bordering motor tracts. Next, a bipolar probe was used to assess the bipolar electrostimulation threshold at the same location, and a neuro-navigation system was used to mark these locations. The respondent myotomes at each location was documented, as well as the neuromonitoring MEP responses. Postoperatively, the distance between the stimulated marked location, resection borders, and the motor brain structures were assessed. Analysis probed the differences between monopolar and bipolar thresholds in mapping cortical and subcortical motor system and their association with motor neuromonitoring and postoperative motor function. Results A prospective intraoperative analysis was conducted on two patients undergoing resection of intra axial tumors at the authors' institution in January 2021. The resection was performed by all clinical standard procedures. Following the resection, additional stimuli were applied by the bipolar probe, to assess the accuracy of the threshold that was needed to evoke a clinical motor response. We found that the bipolar threshold was higher than the conventional threshold used by the monopolar probe in the borders of the resection. Conclusion Our findings suggest the bipolar stimuli can give more accuracy in determining the motor function of certain anatomical structures which can lead to better results in the maximal safe resections goal and allow neurosurgeons another intra operative tool to achieve the best outcomes for their patients.
P11.02.A Gliotarget: a Danish nationwide phase I/II platform trial focusing on individualized targeted treatment for newly diagnosed glioblastoma patients based on genomic profiling
Authors: V N Fougner, T H Urup, B Hasselbalch, U Lassen, H S Poulsen
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The survival in glioblastoma has been unchanged since 2005. The introduction of targeted treatments, which have improved survival in several cancers has yet to influence the treatment of glioblastoma. In Gliotarget, we will individualize the targeted treatment, and give it in the primary setting alongside standard therapy with the intention to improve the likelihood of effect. METHODS Gliotarget is a biomarker enriched phase I/II platform trial with initially 4 predefined biomarker selected arms and one control arm. All patients receive standard therapy with concomitant radiochemotherapy and adjuvant temozolomide. The experimental treatment is given alongside the adjuvant temozolomide. Molecular analysis, including Whole Genome Sequencing, is performed on all patients, to identify actionable biomarkers. Gliotarget includes newly diagnosed IDH-wt glioblastoma patients. In addition, to exclude the patients where the inherent poor prognosis might conceal the drug efficacy, the patients must have a 50% probability of being alive 12 months after initial surgery, according to a prognostic model developed in our institution. The sample size is calculated with Simon’s two-stage design using treatment effect at 9-months progression free survival (PFS9). We anticipate 9 patients for stage one and 24 in total, for each arm. Treatment effect is defined as 65% of the patients in an experimental arm reaching PFS9. For the survival analysis, supplementing the control arm data with leveraged external controls taken from our prospectively registered database will decrease the probability of false positive results. CONCLUSION Gliotarget complements the field of ongoing platform trials with its distinctive trial design. The chosen biomarkers and treatments will be presented at the 2022 EANO meeting. Enrollment is set to open in Q4 2022.
P15.08.B Intraoperative confocal laser endomicroscopy of brain tumors - potential and challenges from a neuropathological perspective
Authors: T Maragkou, K Quint, B Pollo, E Hewer
Journal: Neuro-Oncology (2022)

Abstract Background Intraoperative consultation, usually in the form of a frozen section, is an integral part of current neuropathology practice. Typical indications include determination of specimen adequacy, intraoperative diagnosis and distinction between tumoral and non-tumoral tissue in diffusely infiltrating gliomas in tumor periphery. The latter is currently limited by the fact that typically not all potential regions of interest can be sampled for frozen sections and the turnaround times of frozen sections usually do not permit multiple repetitive assessments. The commercial availability of a clinical-grade in vivo laser endomicroscope for neurosurgical applications may have the potential to change this and to permit a microscopic analysis in near-real time, which in turn may have a significant impact on resection strategies for brain tumors. In this work, we investigate the potential role of CLE in neurosurgery and the transferability of histological criteria to confocal imaging. Material and Methods The potential role of CLE in neurosurgery in comparison to other techniques for intraoperative tumor assessment was determined by analyzing common intraoperative neuropathological workflows and identifying unaddressed opportunities. The transferability of the histological criteria from standard histology to confocal imaging was achieved by analyzing matched image pairs (standard histology and CLE) from several common tumor entities. Results We identified the time gap between specimen resection and the availability of the frozen section results as an important application for intraoperative CLE imaging in neurosurgery. Importantly, neuropathologists could assess tissue in near real time in an unlimited number of digital biopsies prior to resection, which adds a potent new tool to the neurosurgical armamentarium. CLE images revealed features similar to already known tissue architecture/morphology seen in standard histology, which correlated well in matched histological images. Unique aspects of individual cells and other surrounding tumor tissue elements were observed in vivo while the CLE probe acquired images throughout its focal-depth range. Conclusion Widespread application of CLE may have a major impact on neuropathologists' role in intraoperative diagnosis and bring along both opportunities and challenges. For broad clinical adoption, strategies for histological criteria validation as well as for determination of diagnostic accuracy need to be developed.
P07.08.B Surgical management of recurrent lower-grade gliomas: analysis of oncological and functional outcomes and associated factors
Authors: L Gay, M Rossi, T Sciortino, M Conti Nibali, M Simonelli, P Navarria, R Rudà, R Soffietti, L Bello
Journal: Neuro-Oncology (2022)

Abstract Background Presently, there are no clear evidence-based recommendations for the surgical management of progressive or recurrent lower-grade gliomas (LGGs). In our work, we evaluated the oncological (PFS, OS) and functional (neurological, neuropsychological, quality of life evaluation) outcomes of a series of LGGs treated in a 5-year period. The aim was to identify clinical, imaging, and molecular factors, associated with better outcomes, to be implemented in the treatment decision making process. Material and Methods In our retrospective analysis, 738 recurrent LGGs were included (follow-up 7.9 years; IQR:6-9); 550 were surgically treated, 495 with open resection (with brain mapping techniques), and 55 with tumor biopsy (with frameless stereotactic technique). Results Overall, 521 patients (70.6%) recurred. Of those treated with open resection 63.5% relapsed. Tumor progression was histologically confirmed in 72.5% of cases, no valuable tumor (effect of treatment) in 27.5% of cases (particularly in cases previously treated with RT and CHT), histo-molecular conversion (astrocytoma instead of oligodendroglioma diagnosis) in 7.5% of cases, malignant transformation in 38.7% of cases. Among the clinical (patient functional status, previous PFS, previous EOR, previous CHT and duration of CHT, previous RT), imaging (type of recurrence, i.e. typical versus atypical, speed of growth, contrast enhancement), and molecular (IDH, codeletion, ATRX, MGMT, tumor grade, CDNK status) factors analyzed, longest PFS of recurrent tumors was associated with patient functional status, previous PFS, previous EOR, speed of growth (&amp;gt;6 mm/year), atypical type of recurrence, tumor grade, presence of codeletion, and CDNK status. Best functional outcome associated with surgical resection, EOR, and tumor grade; worst functional outcome with RT and malignant transformation. Longest OS associated with previous EOR, surgical resection, tumor grade, presence of co-deletion. Malignant transformation was associated to previous EOR. Among patients submitted solely to tumor biopsy, changes in MGMT methylation status and in IDH status were observed in 65.3% and 5% of cases, respectively. Modification in IDH status was associated with atypical (distant) type of recurrence. New histo-molecular profile helped in the treatment decision making process. Conclusion Surgical resection of recurrent LGGs is associated with longer PFS and OS. Tumor biopsy should be considered, when surgery considered unfeasible, to tailor adjuvant treatment.
P12.13.B Investigating the tumor - immune cell crosstalk in<i>ex vivo</i> glioblastoma models
Authors: M Rezaeipour, E Klein, C Dording, S P Niclou, A Golebiewska
Journal: Neuro-Oncology (2022)

Abstract Background Immunotherapy is a promising therapeutic approach to fight cancer by activating the immune system. Multiple immune-based strategies are under development that aim at recruiting or re-activating cellular components of the immune system. While immunotherapies have recently revolutionized cancer therapy, they have shown so far little therapeutic success in glioblastoma patients. To enhance the efficacy of novel strategies, we need to better understand the immunogenic status of glioblastoma cells and their cross-talk with immune cells in different microenvironmental niches. Material and Methods We assessed expression of molecules related to antigen processing and presentation as well as immune checkpoints in patient tumor databases as well as in a series of glioblastoma patient-derived organoids, 3D stem-like cultures and adherent cell lines under varying microenvironmental conditions (varying oxygen levels, inflammation). We further established an allogenic co-culture protocol for glioblastoma organoids with immune cells isolated from HLA matched donor blood, allowing for the functional assessment of the crosstalk between tumor and immune cells. Results Analysis of a large cohort of patient tumors and patient-derived glioblastoma preclinical models shows inter-patient heterogeneity at the level of components of major histocompatibility complex (MHC)-MHC-II, immune checkpoints. Glioblastoma cells in general express MHC-I machinery, albeit at different levels. MHC-II and immune checkpoints are variably expressed across glioblastoma cells. Different tumor microenvironment conditions, including hypoxia and interferon-γ, impact the expression of immune-related molecules. Upon co-culture, HLA-matched donor-derived T cells integrate well into the core of glioblastoma tumor organoids and display reciprocal crosstalk with tumor cells. Conclusion Assessing antigen presentation and immune cell responses at the functional level are key to improve patient-specific responses to immunotherapies. Advanced glioblastoma organoids incorporating the immune compartment appear as clinically-relevant models for ex vivo efficacy studies.
P17.13.A Verteporfin inhibits autophagy in glioblastoma cell lines
Authors: G Casati, L Giunti, A Iorio, A Marturano, I Sardi
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis, characterized by a high cellular heterogeneity and invasiveness. Multi-drug resistance (MDR), the blood brain barrier (BEE) and DNA repair systems let the survival of tumor cells, making the treatment with chemo and radiotherapy not effective. Autophagy is a physiological mechanism that allows the recycling of damaged proteins and organelles, in order to protect the correct cell turnover. However, in GBM this process promotes survival and proliferation in stressful conditions such as after a chemo and / or radiotherapy treatment. The Hippo pathway is an extremely important molecular signaling because it is involved in various tumorigenesis processes, for instance the epithelium-mesenchymal transition (EMT), in the increase of stemness, mechanotransduction and chemoresistance. Material and Methods The modulation of autophagy was evaluated in GBM cell lines (U87MG, T98G and A172) exploiting a fluorescent detection that allowed the quantification of the autophagosomal activity present into the cell lines. The rate of autophagy was assessed after the cell lines pharmacological treatment with Hippo pathway inhibitors, Verteporfin 2uM (VP) for 24h, Latrunculin 0,5uM (LAT) for 3h and Cytochalasin 1uM (CIT) for 3h, with Doxorubicin 0,5uM (DOX) for 24h and with the drugs combination (DOX-VP, DOX-LAT and DOX-CIT). Moreover, the expression of the autophagy marker LC3II / I was evaluated in all three GBM cell lines by Western Blotting (WB) experiments. To perform this technique, the cells were treated with DOX and Hippo pathway inhibitors respecting the pharmacological treatment previously used. Then, the proteins were extracted, quantified and finally the WB was performed. Results The results obtained showed that the three GBM cell lines without any drugs were marked by high levels of autophagy, similar to the cells treated with Rapamycin, an autophagy inducer. Moreover, the autophagy rate was definitely reduced after treatment with VP and DOX-VP in all three cell lines, including the chemoresistant T98G. Conversely, the other two Hippo pathway inhibitors (LAT-CIT) and DOX did not significantly change the rate of autophagy. The expression of LC3II / I was particularly low after treatment with VP and DOX-VP in all three cell lines while the other two inhibitors did not significantly change its expression. Conclusion In conclusion, these data demonstrated that the three GBM cell lines (U87MG, T98G and A172) are characterized by high levels of autophagy and the inhibition of the Hippo pathway with VP and especially the combination DOX-VP reduced the activation of this protumoral molecular mechanism in GBM cell lines.
P17.09.A Regorafenib and Re-irradiation: analysis of clinical outcomes and toxicities in patients with recurrent glioblastomas
Authors: S Fiorelli, G Campisi, I Angelicone, F De Giacomo, C Ricciardi, V De Sanctis, A Ascolese, M Osti
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is the most common and aggressive primary brain tumor in adults.The aggressiveness and poor prognosis related to this disease join to the limited available treatment options. The current standard of care involves surgical resection followed by concomitant radiotherapy and chemotherapy. At recurrence, no standard treatment exists and there are no guidelines to facilitate decisions in the recurrent setting. Available options include re-operation, re-irradiation, systemic therapy, alone or in combination. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. Regorafenib (Stivarga) is an inhibitor of several kinases involved in the mechanisms that regulate neoangiogenesis processes, through the inhibition vascular endothelial growth factor (VEGF) receptors and the modifications of the tumor microenvironment; specifically, Regorafenib binds and stabilizes PSAT1 (phosphoserine aminotransferase 1). The dual regulatory mechanism underlying PSAT1-induced autophagy arrest accounts for the superior anti-GBM effect of Regorafenib compared with Temozolomide. Material and Methods 15 patients with documented disease progression after surgery followed by RT and TMZ were assigned to receive regorafenib (REG) 160 mg once daily for the first 3 weeks of each 4-week cycle. All patients received prior radiation therapy (RT) to a median dose of 60 Gy (range 40.05 -60). Median time to retreatment after prior RT was 16 months (range 14-33). Tumor volumes ranged from 81.7 cm3 to 422.4 cm3 (CTV) and from 112.7 cm3 to 422.4 cm3 (PTV).3 patients (20%) received concomitant reirradiation with a radiation dose of 37.5 Gy in 15 fractions of 2.5 Gy. Results the median follow-up was 9.5 months (range 5-22). The overall survival and the progression-free survival rates were 53,8 %, and 46,6 % respectively at 2 years. In 53% the symptoms were stable. Only one patient developed late toxicity: acute pancreatitis (Grade I) regressed on interruption of Regorafenib. No other neurological deficits occurred during follow-up. At last follow up 60% of patients were alive. Conclusion we report our experience with Regorafenib, administered in patients with rapid progression after the end of postoperative radio chemotherapy treatment. Regorafenib might be a new potential treatment option for recurrent glioblastoma: it was well tolerated also in cases of combined treatment with reirradiation and appeared effective. Other studies will be necessary to evaluate and confirm the role of Regorafenib in glioblastoma patients and the potential effectiveness of the combined therapeutic strategy: Regorafenib-reirradiation.
P10.16.A Repurposing thioridazine as a novel treatment of melanoma brain metastasis
Authors: E Moen Taule, T Wikerholmen, E Rigg, K Sarnow, J Wang, F Thorsen
Journal: Neuro-Oncology (2022)

Abstract Background Melanoma shows increasing incidence and has the highest propensity to metastasize to the brain of all primary malignant tumors. Untreated, the median survival time is 2-3 months after diagnosis, while aggressive treatment extends survival to only 4-12 months. Even though targeted therapies and immunotherapy has changed the therapeutic landscape, many of these patient relapse. In this respect, drug repurposing, using old drugs for new purposes, has had several successes for other diseases. The anti-psychotic drug thioridazine (THD) is a dopamine receptor 2 antagonist, with properties to cross an intact blood brain barrier, has shown promising effect on melanoma cells that has escaped prior treatment and on cancer stem cells. However, the therapeutic effects on melanoma brain metastasis (MBM) have not been previously investigated. Material and Methods All experiments were done on MBM cell lines (H1, H2, H3 and H10), which were developed in our lab from patient biopsies obtained after surgery. A monolayer viability assay (WST-1) was used to determine IC50 doses. Migration and proliferation after treatment was studied by IncuCyte live cell imaging. Colony forming properties and the ability of cells to grow in an anchorage free environment after THD treatment was investigated using a 2D clonogenic assay and a 3D soft agar model. Potential drug effects were also studied on normal human astrocytes (NHA) and on fetal rat brain organoids (FRBO), using a Live/Dead viability kit and confocal imaging. Apoptosis and necrosis was studied by Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis after 72 hours of treatment. Results THD shows a strong cytotoxic effect on MBM cell lines. Cell viability studies showed that THD exerted a dose-dependent inhibition of tumor cell viability (IC50 doses 9-12 µM), while NHA tolerated similar drug concentrations. Tumor cell migration and proliferation were almost completely inhibited with concentrations below the IC50 doses. An inhibition of clonogenic formation and 3D growth was also observed. Bright field microscopy showed changes in MBM morphology in monolayers, but FRBOs were intact after drug treatment. Further, apoptosis in MBM cells was induced after treatment with THD. Conclusion Our preliminary data shows that THD has a strong selective cytotoxicity in MBM cells with minimal effects on NHA and FBRO.